Progressive Multifocal Leukoencephalopathy (PML) is a deadly opportunistic infection of the brain caused by the polyomavirus JC (JCV), which occurs in immunosuppressed individuals. There is no treatment for PML, and the incidence of this disease has not decreased significantly in HIV+ patients since the availability of highly active antiretroviral therapy (HAART). In addition, a growing number of organ transplant recipients are also at risk for PML, as well as patients with multiple sclerosis and Crohn's disease treated with the novel immunomodulatory medication natalizumab. The challenges that lies ahead is to harness advances in our understanding of the virological and immunological determinants of JCV pathogenesis and translate them into both pre-diagnostic markers aiming at preventing PML, as well as therapeutic options for this disease, while training the next generation of young physicians in patient-oriented research. In this application, we will: 1) Characterize pre-diagnostic markers of PML;2) Analyze the molecular determinants of JCV latency and reactivation in bone marrow, and determine the phenotype of JCV infected bone marrow cells;3) Determine the role of HLA class I alleles in PML outcome;4) Correlate MRI/1H-MRS, histological, immunological and virological parameters over time with lesion volume, neurological deficit and clinical outcome of the PML patients;5) Study JCV reactivation in MS patients treated with natalizumab, and explore the effect of VLA-4 blockade on JCV-specific CD8+ T cells;6) Characterize the pathogenesis of the JCV variant associated with JCV Granule Cell Neuronopathy (JCV GCN);7) Develop dendritic cell-based immunotherapy for PML; and 8) Explore the antiviral immune response against the polyomavirus BK in the context of HLA mismatched kidney grafts. Opportunities for mentoring young physicians, scientists, junior faculty and students are discussed for each specific aim. These studies will certainly appeal to young individuals interested to launch their careers in the fields of Neurology, Neurolmaging, Infectious Diseases, Virology, Immunology, Hematology, Nephrology and Pathology.